Ladies and gentlemen, thank you for standing by and welcome to the Sarepta Therapeutics Fourth Quarter 2019 Earnings Call. At this time all participants are in a listen-only mode. After the speaker's presentation there will be a question-and-answer session. [Operator Instructions]. As a reminder, today's program may be recorded. I would now like to introduce your host for today's program, Ian Estepan, Senior Vice President, Chief of Staff and Corporate Affairs. Please go ahead, sir.

Thank you so much, Jonathan, and thank you all for joining today's call. Earlier today, we released our financial results for the fourth quarter and full-year 2019. The press release is available on our website at www.sarepta.com and our 10-K was filed with the SEC earlier this afternoon. Joining us on the call today are Doug Ingram, Sandy Mahatme, Bo Cumbo, Dr. Gilmore O'Neill and Dr. Louise Rodino-Klapac. After our formal remarks, we'll open up the call for Q&A. I'd like to note that, during this call, we'll be making a number of forward-looking statements. Please take a moment to review our slide on the webcast, which contains our forward-looking statements. These forward-looking statements involve risks and uncertainties, any of which are beyond Sarepta's control. Actual results could materially differ from these forward-looking statements and any and such risk can materially and adversely affect the business, the results of operations and trading price for Sarepta's common stock. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on Form 10-K filed with the Securities and Exchange Commission, as well as the company's other SEC filings. The company does not undertake any obligation to publicly update its forward-looking statements, including any financial projection provided today based on subsequent events or circumstances. And with that, I'd like to turn the call over to Doug Ingram for corporate update.

Thank you, Ian. Good afternoon and thank you all for joining Sarepta Therapeutics fourth quarter 2019 conference call. In 2018, we defined our vision to become one of the world's leaders in precision genetic medicine to treat rare disease, founded both on our precise and efficient RNA platform and on the build of a gene therapy engine capable of rapidly advancing multiple constructs through development into the patient community. In 2019, we executed, further matured, and brought that vision into greater focus, and in 2020 – through 2020, we will, if successful, realize much of that vision. We have an enormous number of milestones in 2020, but before we discuss them, let us review the progress that we have made in 2019. I will begin with our RNA platform As we announced at the JP Morgan conference in January, our fourth quarter 2019 revenue stands at $100 million. In our third full year since launch, our 2019 revenue was $381 million, a 26% increase over prior year. I will remind you that we have never taken a price increase since launch. So, our growth comes from continuing to serve the Duchenne community. Our 2020 guidance for EXONDYS is $420 million to $430 million. As we are just launching VYONDYS, we will wait until later this year before providing revenue guidance. But you can expect the launch curve similar to that of VYONDYS. In the third quarter, we obtained FDA approval for our second RNA therapy, VYONDYS 53. The approval of VYONDYS was a win for objective, evidence-based decision making. It was a win for hard working professionals at the FDA neurology division that was responsible for this review. And most importantly, it was a win for Exon 53 amenable patients. With the regulatory pathway we confirmed, we submitted our rolling…

Thanks, Doug. Good afternoon, everyone. Over the course of 2019, we advanced the business in several significant ways. We beat revenue guidance for EXONDYS 51, launch another of our RNA medicines, VYONDYS 53, significant bolstered our financial position and struck several new licensing deals, bringing our total number of development programs up to 42. We also struck a partnership with Roche that closed earlier this month, and that brought in $1.15 billion into the company. This collaboration brings significant capital to fully fund our pipeline, including of sharing payments, and it provides us access to Roche's significant expertise and really expand the global opportunity for our lead gene therapy program, SRP-9001. Now, moving to the financials. This afternoon's press release provided details for the fourth quarter of 2019 on a non-GAAP basis, as well as a GAAP basis. The press release is available on Sarepta websites. Please refer to it for a full reconciliation of GAAP to non-GAAP. Net product revenue for the fourth quarter of 2019 was $100.1 million compared to $84.4 million for the same period of 2018. The increase primarily reflects high demand for EXONDYS 51. On a GAAP basis, the company reported a net loss of $235.7 million and $140.9 million or $3.16 and $2.05 per basic and diluted shares for the fourth quarter of 2019 and 2018 respectively. We reported a non-GAAP net loss of $116.9 million or $1.57 per basic and diluted share in the fourth quarter of 2019 compared to a non-GAAP net loss of $58.7 million or $0.85 cents per basic and diluted share in the fourth quarter 2018. In the last quarter 2019, we recorded approximately $15.6 million in cost of sales compared to $13.1 million in the same period of last year. The increase was driven by royalties due to…

Thank you, Sandy. Good afternoon, everyone. Toward our 2019 objectives around execution and our commitment to deliver on our stated goals, I'm pleased to report the following on behalf of the organization. We exceeded revenue consensus expectations for both the fourth quarter and the full year of 2019, totaling $100.1 million and $380.8 million respectively. As Doug mentioned, our 2020 guidance for EXONDYS 51 is $420 million to $430 million. In terms of continuing to serve the community, we know that there are additional patients who may benefit from EXONDYS 51 and we will continue to overcome access and reimbursement challenges to get patients on therapy. Golodirsen, or VYONDYS 53, received an accelerated approval by the FDA on December 12, 2019. VYONDYS 53 treats Duchenne muscle dystrophy patients who are amenable to skipping Exon 53. Acting with urgency and the knowledge that patients were waiting, we launched VYONDYS 53 within 24 hours of FDA approval, just as we did with EXONDYS 51. We submitted all of our compendium, contracting and reporting requirements and vyondys53.com, a critically important resource for families, went live. While we're leveraging our deep knowledge and expertise for the EXONDYS 51 launch, it is important to understand that there will be standard procedures and required reimbursement policies associated with launching a new drug with a unique NDC or national drug code. Our team is prepared to work through these requirements as we have in the past and we anticipate a measured and steady launch trajectory for VYONDYS 53, resembling the launch curve for EXONDYS 51. The only difference is that we are preparing and planning for the amendable Exon 53 space to be competitive. In support of our goal to increase access for VYONDYS 53, we are pursuing a multi-pronged strategy. Although commercial and state Medicaid plans…

Thank you, Bo. And thank you, before Bo, Sandy. And with that, let's open this call for questions.

[Operator Instructions]. Our first question comes from the line of Ritu Baral from Cowen. Your question, please.

Good afternoon. Thanks for taking the question so early and accommodating the rare disease week agenda here in DC, Doug. Appreciate it. Doug, can you let us know when the last patient for gene therapy was dosed? Basically, what is the shortest follow-up period both for micro-dystrophin as well as limb-girdle and can you talk about the safety profile, especially liver, especially platelets that you've seen in that time period for both programs? Thanks.

Well, I can just tell you very broadly that if you sort of backward engineer, we're going to have the – for the 41 patient study, 102, the last patient last visit will be in December. So, if you work backwards, you'll see that the last patient was right at that – it actually might have been the very first week in the 2020. So, that was the first 41 patients dose. We're continuing on an ongoing basis to dose patients on crossover as well if there's a significant number, as I've mentioned to you now. But in Study 102, between the proof of concept 101, between the main 41 patient steady and between the crossovers, we've dosed over 30 patients with active therapy. We have now dosed six patients with limb-girdle, both the previous dose and now the higher dose to limb-girdle. And of course, a lot of that's blinded. So, we'll all see together both the safety and – the full safety and efficacy. But broadly speaking, I will say again, consistent with our preclinical models, we have never seen anything that looks like complement or reductions in platelet counts below the normal levels. So, things continue as they were. Study 102 continues completely uninterrupted. We're making great progress there. The exciting thing about 102 is that we'll have last patient in December and we'll have a readout in the first quarter of 2021. And I will remind you that is a readout not merely on expression and on safety, but also on function using an assay.

Our next question comes from the line Tazeen Ahmad from Bank of America. Your question, please.

Hi, good afternoon, guys. Thanks for taking my question. I just want to ask about PPMO. You've talked about data for this year. Specifically, Doug, what kind of data do you think that we'd be able to see? And can you just narrow the timeline for us on what part of the year that would be? And then, I guess, related to that, assuming that this data looks better ultimately than PMO and that you also do have gene therapy approved, how do you think about the package that you're offering overall to DMD patients, why would they need to be, let's say, on PPMO and gene therapy potentially. Thanks.

Thanks for that. I'm really glad you're asking about PPMO because we're very excited. We're excited about our RNA technology. Generally, we're very excited about what PPMO may be. Of course, we don't have the results yet. I'm going to turn this over briefly to Dr. O'Neill to talk about some of the data that we'll get. Let me get a couple of broad strokes. So, we're targeting the middle of the year for some data. We're continuing to dose escalate. Things look great. We might even dose escalate beyond the middle of the year, but we'll have safety exposure and dosing information by the middle of the year. And I'll let Dr. O'Neill sort of give you some more detail on that. On the broader question about what this might mean for patients if we have both gene therapy and either a current RNA or a next generation version of RNA, PPMO, in the future, that's work we're doing right now. I know that there are a lot of investors that have kind of assumed for planning purposes that there would be great cannibalization of the RNA franchise when gene therapy comes. And if it turns out, in the end, that the gene therapy that we're working on is so profoundly impactful, that it alone is meaningful and that it cannibalizes it, then so be it. We'll thrilled with that answer for patients. But I think there is a lot of hypotheses and some thesis and some literature actually that would support the conclusion that there may be accommodative value of gene therapy and RNA. And I think with the PPMO, as that really was a profoundly significant advancement over our current technology might make that even more meaningful. So, we're doing a bunch of work on that right now. We'll come back likely early next year and provide additional insight and views on what the combination of our RNA technology and gene therapy might mean and there's two things to look at there, obviously, the science of that and of course there's the access and reimbursement related issues that Bo and his team are working on. And with that, I will turn it over to Dr. O'Neill to talk a bit about the information that we'll receive around the middle of this year.

Thanks very much, Doug. Hi, Tazeen. Thanks for your question. What we actually will be looking at, a combined data set in the second quarter from both healthy volunteers, which was a single ascending dosage study and a [indiscernible] multi ascending dose study in Duchenne patients, in which we will have a comprehensive safety data, we will have systemic exposure, blood exposure, we will actually have muscle exposure using muscle biopsy and we'll actually also be looking at some pharmacokinetic data with a particular focus on Exon skipping because these will be short follow-ups at this point.

Thanks very much, Doug. Hi, Tazeen. Thanks for your question. What we actually will be looking at, a combined data set in the second quarter from both healthy volunteers, which was a single ascending dosage study and a [indiscernible] multi ascending dose study in Duchenne patients, in which we will have a comprehensive safety data, we will have systemic exposure, blood exposure, we will actually have muscle exposure using muscle biopsy and we'll actually also be looking at some pharmacokinetic data with a particular focus on Exon skipping because these will be short follow-ups at this point.

Thank you. Our next question comes the line of Joel Beatty from Citi. Your question please.

Hi. This is Shawn Egan calling in for Joel. Thanks for the update today and also for taking my questions. On the DMD gene therapy, I know that you guys have previously said that you plan to have adequate supply to address the market. But in a scenario where supply is limited, are there conditions in the agreement with Roche that dictate how product will be allocated between the US and rest of world? Thank you.

The short answer is we'll know – again, we are trying to get to our goal. And our goal is to ensure at the moment of launch and availability to the community in each of the various regions that we in the US and then Roche with us, outside the US, will go that we'll have adequate supply for patients. Obviously, we've got much more to do with Roche on that, particularly as we think about how broad this could be outside of the US when you have a partner with the resources of Roche. And we'll just plan for them. The real work on – the most significant work, at least for us now, is on the assay development and process development and getting GMP runs and getting buy-in from the agency and commencing this trial. We've built already a significant amount of capacity. We've got standalone site at Lexington, Massachusetts. We've got significantly more already over at Paragon Catalent. And as we do the work and we progress, we need more capacity still. We can certainly do that. We've got a relationship with Paragon alone that would have provided us with that ability to take additional suites and add additional capacity as we proceed. So, we're planning for success and I'm quite confident in our relationship with Roche. We'll both be planning for success.

Thank you. Our next question comes from the line Christopher Marai from Nomura. Your question please.

Hi. Thanks for taking the question. One on MPS III A, your progress there. I was wondering, given the [indiscernible], if you could comment a little bit on the age of the patients that are being enrolled and then perhaps a little bit on the type of endpoints you're going to be looking at and then your confidence in being able to see a difference between, I believe, the natural history [indiscernible]. Thank you.

Chris, thanks for your question. So, I think there were two elements he wants to know about, outcomes and the age of the patients. The study had actually – you can see it on the clinicaltrials.gov, actually requires patients to have at least an age of six months. But the key ceiling for age is really created by a requirement they have a development quotient of 50% or greater. So, that naturally restricts the upper age group there. With regards the outcome measure, I kind of hinted at it, which is the development quotient is the primary outcome measure. And essentially, that is a way of capturing the cognitive behavior development of the children in this trial. And that quotient essentially is, not surprisingly, a ratio determined by the outcome measures in one of two measures – the Bayley scale, which is a development measure for infants and toddlers or the Kaufman Assessment Battery. Each one is used depending on the age of the patient. And then, to your point, yes, we are looking at the outcome versus the natural history, which is again described in clinicaltrials.gov. Thanks for your question.

Chris, thanks for your question. So, I think there were two elements he wants to know about, outcomes and the age of the patients. The study had actually – you can see it on the clinicaltrials.gov, actually requires patients to have at least an age of six months. But the key ceiling for age is really created by a requirement they have a development quotient of 50% or greater. So, that naturally restricts the upper age group there. With regards the outcome measure, I kind of hinted at it, which is the development quotient is the primary outcome measure. And essentially, that is a way of capturing the cognitive behavior development of the children in this trial. And that quotient essentially is, not surprisingly, a ratio determined by the outcome measures in one of two measures – the Bayley scale, which is a development measure for infants and toddlers or the Kaufman Assessment Battery. Each one is used depending on the age of the patient. And then, to your point, yes, we are looking at the outcome versus the natural history, which is again described in clinicaltrials.gov. Thanks for your question.

Thank you. Our next question comes from the line of Brian Abrahams from RBC Capital Markets. Your question please.

Hi. It's Bert on for Brian. Thank you very much for taking our question. I was just interested to get your thoughts on Pfizer's Phase III study design and timing and see, I guess, where you think – how much of a lead you think you have at this point in DMD? And then, after your initial feedback from the FDA on Study 3, have there been any changes to your plan to approach the agency with the 12-month functional data from Study 2 with the three-month expression data from Study 3, presumably in early 2021, to determine the potential for that making up sufficient and filing data set?

Yeah. So, a couple of thoughts. First, on the latter thought, there's nothing in our discussions with the agency that's impacted our broad perspective on the approach, both the 301 and our current Study 102. Obviously, we've taken views of the agency into consideration and made modifications, but they've been modest to date. Going back to the Pfizer posting on clinicaltrials.gov, I'm going to turn this over briefly to Dr. O'Neill who can provide insight into that. Broadly speaking, I will say, of course, that anybody working in this area of Duchenne muscular dystrophy should deserve kudos. This is, of course, and all of us and driving in this direction is a positive. You can imagine our views on our own construct and its value, particularly given the results that we've seen so far, both in safety and in expression. We've had enormous expression as you've seen in the first four patients dosed with our current dosing. And from a functional perspective, I think you've seen all four of those boys at nine months showed significant improvement and improvement over natural history at every single functional endpoint. So, we're very excited about where we are and where we're driving and, certainly, we see ourselves as the leader of Duchenne muscular dystrophy and as the leader of gene therapy for Duchenne muscular dystrophy. But kudos to anyone working in this area. But with that said, I would turn this over to Dr. O'Neill to give you a view on the submission.

Thank you, Doug. As a group of people who are passionate and committed to Duchenne boys and helping them take on this disease, we're obviously always very happy to see the increasing investment and increasing attention of the scientific community, and frankly, the commercial sponsor community in treating Duchenne. I think what's important to say is that we are on track with all our activities with regard to clinical trial site setup. We have very excited investigators, very enthusiastic investigators and patients and are very happy about the progress and the commitment that we are receiving. I think it's also important to see, as our program has evolved, we're seeing some emerging differentiation factors, some of which I'll name, about four. One obviously is our promoter, in which we have a specific promoter, which is both highly efficient and very precise in targeting expression of micro-dystrophin. And why does that matter? Because it targets that expression to [indiscernible] cardiac muscle which are the two critical organs or tissues adversely impacted by Duchenne. And second, as Doug has said, we have seen high degrees of expression of micro dystrophin in muscle in treated Duchenne boys in our proof of concept study. Three, we have not seen counter-activation. And four, and very importantly, with regard to our program, we have fully enrolled the 41 patient, double blind, randomized, placebo controlled study. And we are on track to actually get a readout of its evaluation of the clinical benefit of micro-dystrophin expression into Duchenne boys in the first quarter of next year. Thanks very much.

Thank you, Doug. As a group of people who are passionate and committed to Duchenne boys and helping them take on this disease, we're obviously always very happy to see the increasing investment and increasing attention of the scientific community, and frankly, the commercial sponsor community in treating Duchenne. I think what's important to say is that we are on track with all our activities with regard to clinical trial site setup. We have very excited investigators, very enthusiastic investigators and patients and are very happy about the progress and the commitment that we are receiving. I think it's also important to see, as our program has evolved, we're seeing some emerging differentiation factors, some of which I'll name, about four. One obviously is our promoter, in which we have a specific promoter, which is both highly efficient and very precise in targeting expression of micro-dystrophin. And why does that matter? Because it targets that expression to [indiscernible] cardiac muscle which are the two critical organs or tissues adversely impacted by Duchenne. And second, as Doug has said, we have seen high degrees of expression of micro dystrophin in muscle in treated Duchenne boys in our proof of concept study. Three, we have not seen counter-activation. And four, and very importantly, with regard to our program, we have fully enrolled the 41 patient, double blind, randomized, placebo controlled study. And we are on track to actually get a readout of its evaluation of the clinical benefit of micro-dystrophin expression into Duchenne boys in the first quarter of next year. Thanks very much.

Thank you. Our next question comes from the line of Alethia Young from Cantor Fitzgerald. Your question please.

Hey, guys. Thanks for taking my question. I guess I just wanted to ask a little bit about upcoming limb-girdle read-out. Obviously, you've got a quite good response from the low dose, about 50% expression. Is that, do you think, sufficient? Or if you're able to see more, would you potentially go on to the higher dose? Just kind of help us think about where the plans [indiscernible 0:41:17]?

Yeah, it's a great question. So, again, just to remind everyone, we dosed three patients in our first dose last year. We saw a couple of things. One, the therapy was well tolerated with some elevated liver enzymes. And I guess everyone by now [indiscernible 0:41:37] see elevated liver enzymes. The good news is both in – our micro-dystrophin program and in this limb-girdle program, elevated liver enzymes have responded well to steroids and are manageable and come back to baseline. From an expression perspective, in our first dose cohort, I mentioned in my prepared remarks,, we saw on immunohistochemistry, about 51% protein-positive fibers. Very good intensity which is an important thing to consider. Whenever anyone looks at protein-positive fibers, you should always be asking about intensity as well. I think the intensity here was – if memory is correct – something like 47%. Someone tell me if I'm incorrect. No one is telling me I am incorrect. And then, we saw a western blot about 37% abnormal. And then, on top of that, as you know, we had nine-month functional data from these three children. And the good news is every child and every functional measure was improving. So, what are we doing now? We're doing one dose higher, 4x that dose. So, we can make a dose decision between those two. And we are, I think, in a very good position right now because, from our perspective, from what we've seen, both in animal models and [indiscernible 0:42:51], the expression that we're getting right now and the signals that we're getting right now are sufficient to envision that we have a very transformative therapy for limb-girdle type 2E, and so we want to explore one does higher. And then, we're going to make a dose decision. It's going to obviously be a risk benefit analysis and we're going to look at the benefits and we're going to see – if we see significantly increased expressions with the same safety profile, let's imagine that as one scenario, then certainly we go to a higher dose. If we see about the same expression between the two, then there will be no value to it. And, of course, we're going to have to – we'll have to look at tolerability and safety as well. So, the good news is, I think either decision, the decisions will be made based on the objective evidence. We'll see that evidence in the second quarter. We'll make an official decision in the third quarter. But I think there's no answer that will be a bad one for us. It'll just be objectively driven. And more important than that, I think there will be a good decision in either event for patients that are living with and degenerating from limb-girdle type 2E.

Thank you. Our next question comes from the line Matthew Harrison from Morgan Stanley. Your question please.

Hi. This is Max Skor on for Matthew Harrison. Regarding the limb-girdle 2E program, could you provide an update on discussions with regulators? Has your view changed at all on a potential accelerated approval pathway? Thank you very much.

So, we just started that process. I think we may have mentioned at the JP Morgan Conference that we've just opened up the dialogue with the agency. We're envisioning that this is going to be a process, going to take a dialogue in education and fairness to the division. One of the things that makes this study and this focus on limb-girdle so compelling is that there are no therapies for it. And because there are no therapies for it, it is not characterized as well as, for instance, Duchenne muscular dystrophy. So, education is part of this process. So, we've got an ongoing dialogue with the FDA where we'll share information, we'll dialogue, we'll come to the right development regulatory approach and we have some time to do that because, at the same time, we've got to do the assay development and the process development and we've got to build GMP material. Our goal is to actually have GMP material released by the end of this year. So, we want to complete that discussion before the end of this year, have a regulatory and development pathway developed by the end of this year and started trial by early next year. Our view remains the same, which is that, for an ultra-rare disease like limb-girdle 2E, where this is a gene therapy and gene therapy here intends to insert a gene that codes for the actual native unaltered protein, a structural protein and a monogenetic disease distinguished by the fact that it is a missing protein that is causing degeneration and death in these children that we should be able in dialogue with the agency to come with the agency to an efficient pathway to bring these therapies to these patients as fast as possible and reasonably considered in light of the constraints that come from dealing with a rare – very ultra-rare and heterogeneous disease. So, a long-winded way of saying we have more dialogue with the agency to have and we'll have a good answer on that by the end of this year.

Thank you. Our next question comes from the line of Gena Wang from Barclays. Your question please.

[indiscernible] for Gena Wang. Congratulations on the updated progress and thanks for taking my questions.

I'm sorry. I apologize. We cannot hear you. Apologies for that.

Can you hear me okay?

Indeed, we can.

Hello?

Yeah. We can hear you now. Thank you.

Okay, great. I guess my question on modeling, I guess how should we think about the impact of the Roche O-US deal on OpEx over the next few years? For example, I think your R&D 2019 was roughly $560 million. Like, how much of that is attributed to the DMD gene therapy and how should we think about modeling cost savings based on the cost sharing payments?.

I'm going to turn this over to Sandy, but just to remind everyone on the call, so that – the people who track. The relationship that we've entered into Roche has another component. We had an upfront payment that was between a fee and a premium-based equity purchase just shy of about $1.2 billion. We have additional milestone payments along the way, about $1.7 billion, if I'm not mistaken. We have significance mid-teen royalties associated with revenue ex-US – net sales ex-US upon rolling that out ex-US. And then, we have cost sharing. And so, the cost sharing is that – from the execution of the agreement, actually. Not the closing of the agreement. But from the execution of that agreement, Roche is responsible for half of all of the global expenses for a development program for our micro-dystrophin program, SRP-9001. And then, to the extent along the way, there was any additional ex-US required studies, Roche should be 100% responsible for that. And so, with that, Sandy, do you want to comment on its impact on the burn rate over the next year?

Yeah. So, thanks for the question. In terms of the burn rate, to your question, the Roche deal should bring us cost sharing payments and that'll help with the burn rate, about $75 million to $100 million this year and in the next few years. But aside from that, the Roche deal is primarily about bulking up our finances. It gives us a significant longer cash rate because it's almost $1.2 billion. It brings in – in addition to PR, we also add another $110 million to our balance sheet. But I don't think there should be a significant enhancement to the modeling, that work that you'd be doing in terms of modeling out the cash spend. So, just to talk about the cash spend, if you remember, last year, we had almost $300 billion of business development deals, primarily due to the $170 million we spent on Myonexus. In addition, we had also guided that we will be investing heavily in gene therapy, both in 2019 as well as in 2020. I think we had indicated about $600 million to $650 million of spend. And that's really where the bulk of our spend is because of business development and gene therapy manufacturing. In addition, in anticipation of a VYONDYS approval, also bulking up our inventory for a potential casimersen approval, this is another area that from an R&D and manufacturing perspective that we are directing some of our spend. Aside from that, I don't think our core spend should increase dramatically from what you saw in the fourth quarter. Just going back to your question, I don't think the Roche transaction significantly impacts what you're modeling aside from the cash runway that we have.

Thank you. Our next question comes from the line of Debjit Chattopadhyay from H.C. Wainwright. Your question please.

Hey, good afternoon. So, first clarification on the [indiscernible 0:50:29] program. I believe the update will be 12-week biopsy. So, if that's the case, how would you set expectations in terms of dealing [indiscernible 0:50:39] expression? And number two, for the limb-girdle program, would you automatically expect a dose dependent increase in beta-sarcoglycan, given that historically when we look at the XLMTM program from Audentes, a 2x increase in dose did not necessarily translate into more protein, but provided a much better morphology and higher genomes per cell, so that should give more durability. So, just kind of thoughts around what the expectation should be for both the dystrophin in PPMO and the protein expression for limb-girdle muscular dystrophy. Thank you.

Okay. I'm going to give the second question to Louise. But before I give her, I'll touch briefly on the PPMO results. So, you are exactly right. It's 12-week biopsies. And so, the expectation on dystrophin shouldn't exist because we aren't even going to look at for dystrophin at this early stage. As you may recall, for dystrophin expression, for our PMO, it was a 48-week expression before we really started looking to see the expression. So, this is early for dystrophin production. We will see Exon skipping. So, that will be a strong [indiscernible 0:51:48] to the kinds of dystrophin that you would see over time as it builds over time. But the best – and that's fine because the actual value of this update, this real significant kind of go/no-go on PPMO is frankly dose and safety. So, to remind everyone of what the PPMO was about. Our RNA technology has – the PMO, the base PMO, two things about it that have been very laudable. It's precise and it's safe. It creates Exon skipping and it creates dystrophin and it's very safe and safe at even – at high doses. It has a limitation associated with it. That limitation is that it's a neutrally-charged molecule. It gets into cells passively and that's a limitation. Our goal with the PPMO is to reduce – is to remove that limitation by using a positively-charged peptide that would – and interacts with negatively-charged protein glycans and drags the PMO into the cell in greater abundance. Animal models tell us that it works brilliantly at least in animal models doing that. And then, if we can get to the right doses, we get very high increases in Exon skipping and, therefore, in dystrophin production. And, literally, at the right dose, you could get as much as an order of magnitude increase. So, real opportunity to be a significant improvement. The one significant question for us is that, can we get to those doses? Can one actually get to the kinds of doses that we would believe over time would develop dystrophin significantly greater than the PMO? And that's what we will have insight into by the middle of this year as we will have safety insight, some exposure insight, Exon skipping insight and we'll have a view on our ability to get to those doses and then we can envision what dystrophin would look like if we looked out a year or so. And with that, I will turn over to Louise to answer some of the questions about the limb-gridle.

I think the question was around – would we expect to see a higher expression at this higher dose, given the preclinical data. So, based on our non-clinical data, you're right to say that we typically don't see changes in expression unless you're at a three-fold or a half log higher dose. So, in this case, we're at a fourfold higher dose in our high dose cohort. Based on our non-clinical data, we would expect to see higher levels of expression. Getting back to Doug's point, we see very good levels of expression. 50% in our low dose. And this is already a transformative dose. We would, based on the non-clinical data, expect to see above that, but this will be a decision based on both safety and efficacy in the end, and we'll look at the data collectively. I think, to your point about higher doses, since our high dose in limb-girdle is equivalent to micro-dystrophin, we're quite happy with where we'd be at. If you were pushing the dose even higher is where you might end up seeing saturation and you might not be increased levels of expression. So, in the dosing levels that were all based on non-clinical data, we feel like we're in a very good range to see increased expression.

Thank you. Our next question comes from the line of Anupam Rama from JP Morgan. Your question please.

Hey, guys. Thanks so much for taking the question. Just a quick one from me. I guess following on some of the limb-girdle questions, it sounds like we're going to have a pretty good look in 2Q of kind of expression and then safety and other factors. So, what's that incremental work that needs to be done between the 2Q update and then when we get sort of dose selection? Thanks so much.

That's a great question. Not a ton. So, we're going to look at that data and we'll have it presented at a medical meeting in the second quarter. We just want to make sure that we're thoughtful, that we make sure we've looped in the DSMB in the process and the like. So, honestly, there's not a ton of work to do from reviewing the data and releasing the data to the actual dose selection, but we just want to make sure for technical reasons that we don't over-promise and that we can make a formal dose selection in the third quarter. So, not an enormous amount of work.

Thank you. Our next question comes from the line of Salveen Richter from Goldman Sachs. Your question please.

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Yeah. So, on that, the short answer is yes. We are still progressing well. In fact, this is a – Study 301, to remind everyone, is a significant international multicenter trial. So, we also believe there's going to be significant demand for that trial. We'll be recruiting, I think, briskly when that study starts. So, we feel that, right now, we've got a lot to do. So, it is always risky, predicting the future, but we feel good that we'll be in a position to look at both functional data out of 102 and, at the same time, look at with respect to a subset of 301, an appropriate subset of 301 expression and safety and CMC related work in early 2021. So, we think we're on track.

And if I may intervene just for a second, Doug. I just want to make sure it's quite clear, the last patient into 102 has already occurred. We're talking the last patient last visit. In question, it actually implied that was last patient in. Essentially, it's the last patient last visit for the one-year functional data. Just want to be sure the everyone is clear on that.

Yeah. So, 102 was – the bulk of 102 was all dosed in 2019. As you know, it was a 40-patient study. It's now a 41-patient study. One patient was dosed in the early 2020 and that will result in the last patient last visit in December. We'll be able to compile that information unblinded and have those results in the first quarter of 2021. And at that same time, if everything goes to plan, we'll also – we should also have expression, CMC and safety data from a subset of Study 301, which is the commercial material trial.

Thank you. Our next question comes from the line from Vincent Chen from Bernstein. Your question please.

Great. Thank you very much for taking the question. On the manufacturing process for your DMD gene therapy, what are the major analytical assays that are remaining to be developed or finalized? And one specific question, what is the potency assay that you use? And have regulators indicated it's satisfactory or is that still being sorted out?

Louise, you want to touch on that question?

All of the release assays have been developed. They're just in final stages of validation. So, currently, we're using a in vivo potency assay with an in vitro potency assay in development.

Thank you. Our next question comes from the line of Whitney Ijem from Guggenheim. Your question please.

Hey, guys. Just a quick from me. And sorry if I missed it. But for the MPS III A program, I think you said 17 patients treated. Can you remind us what the timeframe for the primary endpoint is? And are there any interims or any potential to get kind of an interim read on that, given you have treated a significant number of patients there? Thanks.

Yeah. So, the current protocol has – it's a 20-patient study. Our goal is to have all the patients dosed before the middle of this year. We're, obviously, well on the way towards that. 17 of 20 already dosed. It's against the natural history cohort. It's a two-year study with a one-year interim. So, there is a chance of an interim look at the data in the middle of 2021.

Thank you. Our next question comes from the line of Joseph Schwartz from SVB Leerink. Your question please.

Good afternoon. Thanks for taking our questions. This is Dae Gon dialing in for Joe. Just a question and a follow-up, if I may, regarding your PMO filing strategy. So, with your rolling NDA submission initiated for casimersen, following your golodirsen experience, I was wondering if there is any additional requirements to submit that NDA or any particular commitments on your part, either prior on or after the potential approval? And sorry if I missed this, but can you clarify the guidance for the mission 51 confirmatory trial for eteplirsen. I understand ESSENCE is due to complete by 2024, but I wanted to get the number for mission 51 please.

So, going to the PMO strategy, the short answer is no. We had a very positive, very thorough review from the neurology division at the end of which the neurology division firmly recommended the approval of that therapy. And, of course, while there was a delay, it got that approval for us, and so we're going to follow the same pathway. For casimersen, we are in the midst of rolling the NDA. We should have that rolling NDA completed in the second quarter. Then we'll have our PDUFA date. We'll be providing updates along the way. With respect to eteplirsen, I apologize I missed the exact question. The short answer with eteplirsen, just to remind everyone is that we have a confirmatory study with respect to eteplirsen. It really is two studies. It required, first, a healthy human volunteer study. I would remind everyone that this is a bit of an unusual confirmatory trial, but if you imagined a normal confirmatory trial using a placebo control, you would have the current dose approved versus a placebo control, this is different. This is our current dose versus an escalating higher dose of eteplirsen, to really ask the question if even higher doses of eteplirsen would confer additional benefit over the benefits already achieved with the current dose of eteplirsen. That's required – because those doses were not yet approved, that required, as a predicate, a healthy volunteer study to be conducted to ensure that it was safe. And that was completed and read out and it was safe and we've commenced study for [indiscernible 1:02:54] and we're on our way with it. That was a very, very specific question and the short answer is we're on our way. Obviously, it'll take some time to complete that study.

Thank you. Our next question comes from the line of Tim Lugo from William Blair. Your question please.

Hey, this is Lachlan on for Tim. Thanks for taking the question. Just wondering if you could provide an update on the number of patients that have enrolled in the second site, the micro-dystrophin study at UCLA and whether you've sort of seen or heard any differences in the experience there compared to dosing in the prior patients at Nationwide, especially as it pertains to safety and tolerability?

Sure. Answering your first question first, the bulk of the patients, obviously, were enrolled and dosed at Nationwide Children's Hospital under Dr. Jerry Mendell as the – he had the bulk of the patients before we had increased the end of the trial from 24 to 40 and what became 41. So, the bulk of the patients were at Nationwide. And answering your question, the answer is no. We have heard of no significant differences in experience between the two sites.

And I'll just to add that, of course, this is a blinded study. So, the blind has been maintained. And so, when we talk about the experiences, the experience at the site level, we can't comment on the safety or efficacy experience as that data remain blinded.

Sorry, that was Gilmore intervening.

We recognize your accent.

Thank you. Our next question comes from the line of Liisa Bayko from JMP Securities. Your question please.

Hi. Thanks for taking the question. Guys, you seem a little hesitant on the commercial site Study 301, can you maybe comment – are you tracking? Is everything going as planned thus far? And just to clarify, are you expecting GMP product to be available in July? Or is that when the study will actually start enrolling? If you could just clarify that. Thanks.

The short answer is the team is doing brilliantly. I can give nothing but kudos to our technical operations team and our clinical operations team in progressing towards the commencement of Study 301. We've done great work from a process development, analytical development and site readiness. So, we're tracking right now. And we will have GMP material released in July. The precise date that we will commence the trial is predicated on three things. It is certainly predicated on having that material available. That is an enormously significant part of this and that's why we were so excited to be achieving commercially viable yields by the end of 2019. And the fact that we were able to start engineering runs was exciting for all of us. The idea that we were able to start GMP runs was exciting for us as well. And, of course, we've built an enormous amount of capacity to be ready for that. Then the two other things that we have to do across the way are – we have site readiness. That means we have to get all the staff initiated and trained and the like. I think we're well on the way to getting all of that done and the team's very focused on that. And the third thing that we're going to have to do as a predicate is to gather the data and engage with the agency and ensure that we're on the same page with the agency to commence the Study 301. So, much to do, but we have made an enormous amount of progress if one stands back for a bit and considers where we were at the beginning of this journey just a year-and-a-half or so ago. And we're tracking well for the commencement of 301 and we're tracking well for the completion of Study 102.

Thank you. Our next question is a follow-up from the line of Christopher Marai from Nomura Instinet. Your question please.

Hi, yeah. Thanks for taking the follow-up. I was wondering if you can comment perhaps on the Phase III trial and its design for gene therapy product 9001. I guess Pfizer reported their trial design – or recently announced their trial design on clinicaltrials.gov. It appears they are dosing patients with their gene therapy as well as a stable dose of steroids throughout the period of the trial. So, it seems to be on top of steroids. And I was wondering if you can comment on your plans for any regulatory discussions in that regard because, as I recall, you're not dosing on top of regular steroid doses. Thanks.

Boys with Duchenne muscular dystrophy are a standard of care on steroids. So, we would maintain in all of our studies children on regular steroids throughout the study. We also have a protocol to modestly increase steroids against the treatment as a prophylactic, which is typical. So, the Study 301 tracks towards the commencement and we've talked about the design before. It hasn't changed in a significant way. It is currently envisioned to be a 1 to 1 placebo-controlled trial and the main study, 301, is currently envisioned to be four to seven years old. It'll be a multicenter trial as well, obviously, blinded. We will have separate studies as well along the way and we're moving as fast as possible both for them as well. One of those is a study called 303, which is for – a study focused on non-ambulatory patients. We think it's extraordinarily important to focus as well on non-ambulatory patients. Even though I think there's a strong argument that, in the United States, one can't achieve an approval across a broader age group when the mechanism of action would presume that all age groups would benefit even if you study a smaller age group, both for access and reimbursement purposes in the United States as well as for approvals ex-US. It's important that we study a broad age population and we'll do that through Study 303 as well as 301.

Thank you. This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Doug Ingram for any further remarks.

Thank you all for joining us this evening and for your questions. We appreciate them all. As I think everyone can see, we've made a lot of progress over the last few years toward our broader vision of becoming one of the most significant leaders in genetic medicine focused both on RNA and the build of this, what we believe to be, profound gene therapy engine upon which we are working. 2020 will be an enormously important year for us. We've got a lot to do here. And if we're successful in doing it and if science cooperates with us, then we will make an enormous leap towards achieving our vision of bringing a better life to countless patients who are living with, degenerating from and, far too often, dying from rare genetic disease. So, thank you very much for that. I look forward to the opportunity over the course of 2020 to keep everyone updated as we progress. Thanks.

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.